Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 7, Issue 4, 2007

Adenosine is universally expressed in all cells. Adenosine is continually formed and destroyed during general cell metabolism by a series of dephosphorylation steps mediated by specific nucleotidases. Within the cell, adenosine levels are usually low but during times of cellular activity or stress (such as hypoxia, inflammation etc), levels rise markedly as a result of increased enzymatic activity. The net effect under pathological conditions is an accumulation of adenosine outside of the cell. Extracellular adenosine can activate at least four receptors: A1, A2a, A2b and A3; these receptors have vastly different affinities for adenosine and different signal transduction properties. These properties allow adenosine receptors to mediate a wide variety of actions that may also be cell specific; these include neuronal transmission, vasodilatation, growth control and macrophage activation. Adenosine, in clinical terms, is perhaps most recognised for its role in cardiac blood flow and heart arrhythmias and this area of research has been extensively studied. The aims of the theme “The adenosinergic system - from physiology to pathology and therapeutics” in this edition of Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry are to describe some of the less well-known diseases where adenosine action may be implicated. As adenosine accumulates during cellular stress it is entirely reasonable to suggest that it could have a functional role in inflammatory situations such as rheumatoid arthritis, wound healing and respiratory disease. Similarly, adenosine accumulates in hypoxia and could have a role in cancer, particularly in the larger tumours where it is a contributing factor in growth control. Its role as a neurotransmitter is clear but data are emerging on its potential value in neuroprotection and disease control in neurodegenerative conditions such as Parkinson's disease and Huntington's disease. A completely new area of investigation is how adenosine may affect the differentiation and function of bone (osteoblast) cells. The article on animal models, including “knockout animals” (null animals for all four receptors have now been created) is particularly pertinent in trying to understand the precise roles of each of the receptors. The authors, recognised experts in their field, have been asked, not only to describe the role of adenosine in a particular setting or disease but also to consider the clinical aspects in terms of drug treatment and development. In support of this there are a number of companies who have a commercial interest in adenosine and several compounds are now in phase 1 and 2 clinical trials.

In this review the hypothesis is developed, that high concentrations of adenosine are anti-inflammatory and therefore beneficial in inflammatory disease like rheumatoid arthritis. The anti-inflammatory effect of adenosine is mediated mainly via specific adenosine receptors on immune cells that are involved in the disease process. Unfortunately, at least three mechanisms support a decrease in the local concentration of adenosine at the site of inflammation: 1) A decrease in sympathetic innervation, which leads to decreased local release of the cotransmitter ATP at the site of inflammation and therefore to a decreased level of its degradation product adenosine. 2) High activities of the adenosine degrading enzyme adenosine deaminase, which leads to increased degradation of adenosine to inosine and therefore decreases the concentration of adenosine 3) Lower activity of the ATP degrading enzyme 5'-Ecto-nucleotidase, which leads to a slower degradation of ATP to adenosine, also resulting in lower local levels of adenosine present. Therefore, it has to be considered that the optimal treatment for rheumatoid arthritis has to include drugs that specifically target adenosine receptors or the adenosine metabolism to increase local adenosine concentrations. In this respect the mechanism of action of low-dose methotrexate therapy is discussed, which is thought to involve the inhibition of adenosine degrading enzymes rather than antiproliferative effects.

Adenosine is a potent physiologic mediator that is released by cells following such stresses as hypoxia and exposure to reactive oxygen species (ROS). By binding to one or more of four known receptors, A1, A2A, A2B and A3 (all members of the family of G protein coupled receptors), adenosine suppresses inflammation and immunologic reactions. Here we review the expression and functional effects of these receptors on inflammatory cells and discuss the potential use of adenosine receptor agonists or agents that increase local adenosine concentrations in the treatment of inflammatory diseases or promotion of wound healing.

Adenosine is a purine nucleoside of endogenous origin involved in a plethora of biological processes including neurotransmission, muscle contraction, cardiac function, haemostasis, vasodilatation, signal transduction, immune regulation, and inflammation/remodelling through specific stimulation of adenosine receptors. To date four subtypes of adenosine receptors have been identified; these are known as A1, A2A, A2B and A3 adenosine receptors. These are expressed on the cell membrane of a large variety of cell types, including inflammatory and structural cells, but their pattern of distribution, their specific function and affinity can vary in different cell types depending on the tissue milieu. This feature makes the understanding of adenosine regulated mechanisms in the pathogenesis of human diseases extremely challenging. Nonetheless, adenosine and its receptors are known to be pivotal in a wide range of disorders through modulation of specific biological responses in their respective organ systems. Adenosine and its receptors have been recently proposed to play a pro-inflammatory and immunomodulatory role in relation to the initiation and progression of several inflammatory disorders of the airways including asthma and chronic obstructive pulmonary disease (COPD). The objective of this article is to review the role of adenosine-receptor signaling in the respiratory system with special focus on chronic inflammatory airway diseases, such as asthma and COPD.

The A3 adenosine receptor (A3AR) is highly expressed in various human solid tumor cells whereas low expression is found in the adjacent normal tissues. Activation of the A3AR with synthetic highly selective agonists, such as IBMECA, Cl-IB-MECA or LJ529, induces tumor growth inhibition of melanoma, lymphoma, breast, hepatoma, prostate and colon carcinoma cells both in vitro and in vivo. Two molecular events take place upon receptor activation and include: a. receptor internalization and subsequent degradation, followed by decreased receptor mRNA and protein expression level. b. modulation of down-stream signal transduction pathways, including those related to Wnt and NF-κB. Subsequently, the levels of cyclin D1 and c-Myc are decreased leading to tumor growth inhibition. IB-MECA synergizes with chemotherapeutic agents to yield an additive anti-tumor effect and protects against myelotoxicity induced by chemotherapy. Taken together, A3AR agonists may be suggested as a new family of orally bioavailable compounds to be developed as potent inhibitors of malignant diseases.

Adenosine is one of the principal neuromodulators in the brain and acts on four specific receptor subtypes: the A1, A2A, A2B and A3 receptors. Adenosine concentrations normally reached in the extracellular space are in the nanomolar range and may stimulate the high affinity A1 and A2A receptors. Inhibitory effects on neurotransmission are mediated mainly by A1 receptors while excitatory effects are mediated by A2A receptors. Adenosine has an overall net inhibitory effect on neurotransmission. Under normoxic conditions, A3 receptors do not exert a significant effect on neurotransmission and no data are available concerning the effect of A2B receptors. Given its ability to modulate neurotransmission, adenosine plays several physiological roles in the brain. It controls motility, acts as an endogenous anticonvulsant, and affects pain control, sleep, cognition and memory. It is also likely to be involved in the tonic modulation of affective states and consequently in social interaction and aggressive behaviour. Under pathological conditions, adenosine plays an important role in neuroprotective mechanisms interacting with A1 and A2A receptors and more recently there is evidence that A3 receptors are also involved. It has been demonstrated that A2A antagonists may be useful for control of symptoms and potentially for neuroprotection in Parkinson's disease. One possible approach in cerebral ischaemia is that of agents increasing locally the extracellular concentration of adenosine and of using A2A antagonists. Recent data support the putative utility of A2A receptor ligands in Huntington's disease.

The role of ATP in the differentiation and function of bone cells has been well-described, with particular focus on the P2X7 and the P2Y2 receptors. ATP, however, can be rapidly broken down by a series of enzymatic reactions to adenosine and adenosine binds to another family of receptors, the P1 or A receptors. We recently provided the first evidence of adenosine secretion from osteoprogenitor cells, and show that such cells express adenosine receptors and the enzymes that are involved in the synthesis (CD73) and metabolism (adenosine deaminase) of adenosine. Exogenously added adenosine stimulated IL-6 and alkaline phosphatase secretion, but inhibited osteoprotegerin expression, and mineralization of cells in culture suggesting its possible involvement in osteoblastgenesis and osteoblast function. Others have recently shown that 1) adenosine receptor agonists, but not antagonists, protected osteoblasts against H2O2-mediated cell death, 2) extracellular ATP and adenosine play important roles in regulating osteoblast differentiation in human valve interstitial cells 3) the A3 adenosine receptor is downregulated in osteoarthritis and 4) agonism of the A3 receptor inhibited bone destruction in an animal model of arthritis. Collectively, these findings suggest that targeting adenosine pathways may be of value in diseases where there is abnormal bone activity.

The development and characterization of transgenic animal models with genetic manipulation over the last decade has significantly broaded our knowledge of adenosine receptor neurobiology, particularly their involvement in various pathological processes of neuropsychiatric disorders. In this review, we summarize the contributions made to the field of adenosine research by transgenic animal models with either target deletion or over-expression of adenosine receptor subtypes and molecules involved in adenosine metabolism pathways. The available data on the various aspects of physiological (e.g. sleep, motor activity, memory, anxiety, agression and depression and vascular function) and pathological (e.g. ischemia, inflammation, neurodegenerative diseases such as Parkinson’s Disease, Huntington’s Disease, multiple sclerosis, seizures and pain) actions of adenosine as revealed by these transgenic animal models are reviewed. The phenotypes revealed by pharmacological, neurochemical and molecular analyses of these transgenic models into the neuromodulatory function of adenosine receptors in the brain and the homeostatic function of adenosine receptors both in physiological and pathological conditions. These analyses, in many cases, also provided compelling evidence for the phenotypes of adenosine receptor transgenic models that differ from adenosine pharmacological studies, indicating complex actions of adenosine receptors. The complex interplay of adenosine receptors and actions in different cell types and subcellular elements is an important aspect of adenosine’s role that requires new transgenic models designed to target specific brain regions, cell types or subcellular elements. Ultimately these studies should prove important in defining strategies for adenosine-based therapeutical approaches for neuropsychiatric disorders.